title: Thrombospondin 1 precedes and predicts the development of tubulointerstitial fibrosis in glomerular disease in the rat.
abstract: Tubulointerstitial fibrosis is one of the most important histologic features that predicts progression in kidney disease. Thrombospondin 1 is an extracellular matrix protein that can activate latent TGF-beta, a cytokine implicated in the pathogenesis of tubulointerstitial fibrosis. We examined the expression of thrombospondin 1 in several animal models of glomerulonephritis (anti-Thy1 model, aminonucleoside nephrosis, passive Heymann nephritis) that are associated with tubulointerstitial disease. Thrombospondin 1 mRNA and protein were transiently increased in tubular cells, myofibroblasts and some macrophages in areas of tubulointerstitial injury. Thrombospondin 1 expression always preceded the development of tubulointerstitial fibrosis, and correlated quantitatively and spatially with the later development of interstitial fibrosis. Thrombospondin 1 expression predicted the severity of tubulointerstitial fibrosis better than the degree of macrophage or myofibroblast accumulation. Thrombospondin 1 expression was associated with increased expression and activation of TGF-beta1 and decreased expression of LAP-TGF-beta in areas of tubulointerstitial injury. We conclude that thrombospondin 1 is an early marker predicting the development of tubulointerstitial kidney disease. De novo expression of thrombospondin 1 is associated and colocalized with increased expression of TGF-beta1 and decreased expression of LAP-TGF-beta during the development of tubulointerstitial disease in vivo. These data are consistent with the possibility that thrombospondin 1 may be an endogenous activator of TGF-beta.
authors.affiliation: Department of Medicine, University of Washington, Seattle, USA.
authors.forename: C
authors.initials: C
authors.lastname: Hugo
authors.forename: S J
authors.initials: SJ
authors.lastname: Shankland
authors.forename: R H
authors.initials: RH
authors.lastname: Pichler
authors.forename: W G
authors.initials: WG
authors.lastname: Couser
authors.forename: R J
authors.initials: RJ
authors.lastname: Johnson
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000032:analysis / Q000378:metabolism; D000077214:Becaplermin; D001706:Biopsy; D016326:Extracellular Matrix Proteins / Q000032:analysis; D005347:Fibroblasts / Q000473:pathology; D005355:Fibrosis; D015870:Gene Expression; D005920:Glomerular Mesangium / Q000737:chemistry / Q000473:pathology*; D015432:Glomerulonephritis, Membranoproliferative / Q000473:pathology* / Q000503:physiopathology; D007684:Kidney Tubules / Q000737:chemistry / Q000473:pathology*; D008264:Macrophages / Q000473:pathology; D008297:Male; D009395:Nephritis, Interstitial / Q000473:pathology / Q000503:physiopathology; D009401:Nephrosis / Q000473:pathology* / Q000503:physiopathology; D010982:Platelet-Derived Growth Factor / Q000032:analysis / Q000235:genetics; D011237:Predictive Value of Tests; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D019700:Thrombospondin 1 / Q000032:analysis / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000032:analysis / Q000235:genetics
chemical_list: D000925:Anticoagulants; D016326:Extracellular Matrix Proteins; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; D019700:Thrombospondin 1; D016212:Transforming Growth Factor beta; D000077214:Becaplermin